Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27Kip1 at G1 phase
Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27Kip1 at G1 phase
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DOI：
10.1038/ncb1194
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发表时间：
2004-12-01
影响因子：
21.3
通讯作者：
Nakayama, KI
中科院分区：
文献类型：
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作者：
Kamura, T;Hara, T;Nakayama, KI
细胞周期蛋白依赖性激酶抑制剂p27（Kip 1）在细胞周期的G 0-G1转换时通过泛素蛋白酶体途径降解（1，2）。尽管核泛素连接酶（E3）SCFSkp 2与p27（Kip 1）降解有关（3-6），但在Skp 2（-/-）细胞中，G 0- G1转换时p27（Kip 1）的蛋白水解正常进行（7，8）。此外，p27（Kip 1）在G 0- G1期从细胞核输出到细胞质（参考文献9 - 11）。这些数据表明，在G1期存在Skp 2非依赖性途径降解p27（Kip 1）。我们现在描述一种以前未鉴定的E3复合物：KPC（Kip 1泛素化促进复合物），由KPC 1和KPC 2组成。KPC 1含有一个环指结构域，KPC 2含有一个泛素样结构域和两个泛素相关结构域. KPC与p27 Kip 1相互作用并泛素化，定位于细胞质。KPC的过表达促进了p27（Kip 1）的降解，而KPC 1的显性失活突变体延迟了p27（Kip 1）的降解。CRM 1介导的p27（Kip 1）的核输出似乎是KPC介导的蛋白水解所必需的。通过RNA干扰去除KPC 1也抑制了p27（Kip 1）的降解。因此，KPC可能控制p27（Kip 1）从细胞核输出后在G1期的降解。
The cyclin-dependent kinase inhibitor p27(Kip1) is degraded at the G0-G1 transition of the cell cycle by the ubiquitin proteasome pathway(1,2). Although the nuclear ubiquitin ligase (E3) SCFSkp2 is implicated in p27(Kip1) degradation(3-6), proteolysis of p27(Kip1) at the G0 - G1 transition proceeds normally in Skp2(-/-) cells(7,8). Moreover, p27(Kip1) is exported from the nucleus to the cytoplasm at G0 - G1 ( refs 9 - 11). These data suggest the existence of a Skp2- independent pathway for the degradation of p27(Kip1) at G1 phase. We now describe a previously unidentified E3 complex: KPC ( Kip1 ubiquitination- promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING- finger domain, and KPC2 contains a ubiquitinlike domain and two ubiquitin- associated domains. KPC interacts with and ubiquitinates p27Kip1 and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant- negative mutant of KPC1 delayed p27(Kip1) degradation. The nuclear export of p27(Kip1) by CRM1 seems to be necessary for KPC- mediated proteolysis. Depletion of KPC1 by RNA interference also inhibited p27(Kip1) degradation. KPC thus probably controls degradation of p27(Kip1) in G1 phase after export of the latter from the nucleus.